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American Journal of Pharmacogenomics

, Volume 3, Issue 1, pp 31–36 | Cite as

Targeting Mature T Cell Leukemia

New Understanding of Molecular Pathways
  • Yuri PekarskyEmail author
  • Cora Hollas
  • Carlo M. Croce
Genomics In Human Disease

Abstract

The best studied T cell leukemia/lymphoma from a genetic and biochemical point of view is T-cell chronic lymphocytic/prolymphocytic leukemia (T-CLL/T-PLL). This neoplasia commonly shows chromosomal rearrangements at 14q32.1 including translocations [t(14;14)(q11;q32), t(7;14)(q35;q32)], and inversions [inv(14)(q11;q32)]. The investigation of the locus in question at 14q32.1 resulted in the identification of two related genes named T cell leukemia/lymphoma 1 (TCL1) and TCL1b. Both genes are activated in T-CLL/T-PLL by the chromosomal aberrations mentioned above. Mice from a transgenic mouse strain expressing the TCL1 gene under the thymocyte specific lck promoter developed a mature T cell leukemia late in life, thereby demonstrating that over-expression of TCL1 induces the neoplastic transformation of T cells.

Biochemically, Tcl1 protein works as a co-factor of the Akt kinase, a key regulator of antiapoptotic and proliferative signals. Tcl1 interacts physically with Akt, increases its kinase activity and facilitates its transport to the nucleus. The pathogenesis of T-CLL/T-PLL may also involve Nur77, a T cell transcription factor required for T cell receptor-mediated apoptosis. Akt phosphorylates Nur77, thereby blocking its DNA-binding ability and rendering the transcription factor inactive.

The recently emerged insights into the molecular mechanisms of T cell leukemogenesis will allow for the development of specific pharmacological tools for the treatment of these hematopoietic malignancies.

Keywords

Ataxia Telangiectasia Ataxia Telangiectasia Pleckstrin Homology Domain Cell Transcription Factor Vitro Phosphorylation Assay 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

Supported by Kimmel Scholar Award and Special Fellowship of Leukemia and Lymphoma Society to Dr Pekarsky. ## The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

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Copyright information

© Adis International Limited 2003

Authors and Affiliations

  1. 1.Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaUSA

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